Throughout this application, various references are referred to within parentheses. Disclosure of the publications in their entirety are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The present invention relates to a method of (1) diagnosing or assessing the likelihood that a patient is afflicted with renal salt wasting syndrome and (2) diagnosing or assessing the likelihood that a patient is afflicted with or will develop Alzheimer""s disease. The present invention also relates to methods of (1) treating, preventing the onset or slowing the rate of progression of Alzheimer""s disease, (2) treating or preventing onset of renal salt wasting syndrome, and (3) inhibiting apoptosis.
A new medical syndrome, the renal salt wasting syndrome has been described in patients suffering from pneumonia, cancers of the lung, and brain diseases such as primary or secondary tumors, brain hemorrhage, AIDS, and Alzheimer""s disease (J. K. Maesaka et al. Life Sci. 52:1875, 1993, J. K. Maesaka et al., J. Am. Ger. Soc. 41:501, 1993). Patients suffering from renal salt wasting syndrome have low serum sodium (hyponatremia) and low serum uric acid levels (hypouricemia). These patients share low serum uric acid concentrations and a renal tubular transport defect for uric acid which results in an increase in the fractional excretion of uric acid. Renal salt wasting syndrome mimics the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in many clinical parameters except that renal salt wasting syndrome has diminished total body water and sodium. Total body fluids are increased in SIADH and decreased in the renal salt wasting syndrome. Because it is extremely difficult to assess accurately the fluid status of patients that do not suffer from edema, renal salt wasting syndrome patients are frequently misdiagnosed as having SIADH.
The importance of making a differentiation between renal salt wasting syndrome and SIADH is the difference in treatment modalities. SIADH is usually treated with water restriction whereas the renal salt wasting syndrome patients require variable amounts of fluid and salt supplementation depending on the extent of their salt and water deficits. Moreover, large volumes of salt and fluid, particularly water, actually exacerbate the hyponatremia in patients with SIADH which can lead to coma and convulsions. On the other hand, fluid restrictions, a common treatment for SIADH, could worsen the clinical condition of the patient with renal salt wasting syndrome because it exacerbates their underlying depletion of body fluids.
Volume depletion and persistence of the hypouricemia and increased fractional excretion (FE) of urate by the kidneys after correction of the hyponatremia distinguish renal salt wasting syndrome from the SIADH. Since assessment of extracellular volume (ECV) which is necessary to determine volume depletion has been shown to be inaccurate in non-edematous and non-ascitic cases (H. M. Chung et al., Am. J. Med. 83:905, 1987), it was postulated that it might be possible to differentiate renal salt wasting syndrome from inappropriate secretion of antidiuretic hormone by scrutinizing urate metabolism and response of the patient to saline infusion. However, the necessary salt balance studies are believed to be less practical than the simple determination described herein.
The plausibility of a salt wasting syndrome in patients with neurosurgical or possibly active brain diseases lies in the demonstration of natriuretic -apoptotic factor(s) circulating in the plasma of patients with neurosurgical and Alzheimer""s diseases by Maesaka et al. (Life Sci. 52:1875, 1993; J. Am. Ger. Soc. 41:501, 1993). There was a fourfold or greater increase in apoptosis in cultured LLC PK1 cells that have been exposed to Alzheimer plasma as compared to normal and multi-infarct dementia (MID) plasma (J. K. Maesaka et al., J. Am. Soc. Nephrol. 6:740, 1995 (abst.)). However, the identity of this factor is not known and the testing of its presence based on an increase in apoptosis in tissue cultured cells is impractical.
It is an object of the present invention to provide effective methods and kits for diagnosing Alzheimer""s disease and renal salt wasting syndrome.
It is another object of the invention to provide a method of treating, reducing the risk of onset of, or slowing the rate of progression of, Alzheimer""s disease.
It is yet another object of the invention to provide a method to treat or reduce onset of renal salt wasting syndrome.
It is yet another object of the invention to provide a method to inhibit the rate of apoptosis.
It is yet another object of the invention to provide a clinical kit for the quantification of prostaglandin D2 synthase levels, preferably for aiding diagnosis of Alzheimer""s disease and/or renal salt wasting syndrome.
In one embodiment, the invention provides a method of diagnosing or assessing the likelihood that a patient is afflicted with renal salt wasting syndrome, said method comprising measuring the level of prostaglandin D2 synthase in a sample from said patient.
In another embodiment, the invention provides a method of diagnosing or assessing the likelihood that a patient is afflicted with Alzheimer""s disease, said method comprising measuring the level of prostaglandin D2 synthase in a sample from said patient.
In yet another embodiment, the invention provides a method of treating or reducing the risk of acquiring renal salt wasting syndrome in a patient in need of such treatment or reduction, said method comprising reducing -xcex9412prostaglandin J2 levels or activity thereof in said patient.
In yet another embodiment, the invention provides a method of inhibiting the rate of apoptosis in a patient with elevated prostaglandin D2 synthase in the plasma or urine, said method comprising reducing -xcex9412prostaglandin J2 levels or activity in said patient.
In yet another embodiment, the invention provides the method of treating or reducing the risk of onset of Alzheimer""s disease in a patient in need of such treatment or reduction, said method comprising reducing -xcex9412prostaglandin J2 levels, or activity thereof, in said patient, other than by administering a cyclo-oxygenase inhibitor.
In yet another embodiment, the invention provides a diagnostic kit for detecting the presence of prostaglandin D2 synthase in a sample, said kit comprising antibodies to said prostaglandin D2 synthase, and means for measuring prostaglandin D2 synthase:anti-prostaglandin D2 synthase immunocomplexes.
The term xe2x80x9cinhibitorxe2x80x9d as used herein means any agent which reduces the normal physiological effect of an already-formed agent, e.g. by action on the agent itself or by antagonistic effect on a receptor for that agent. EXCEPTION: As used herein, the term xe2x80x9ccyclo-oxygenase inhibitorxe2x80x9d does not include cyclo-oxygenase antibodies.